Asymmetrical Dimethylarginine Antagonizes Glutamate-Induced Apoptosis in PC12 Cells
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Asymmetrical Dimethylarginine Antagonizes Glutamate-Induced Apoptosis in PC12 Cells Xiang-Yu Wang & Jing Zhao & Hong-Wei Yang
Received: 28 August 2012 / Accepted: 25 September 2012 / Published online: 5 October 2012 # Springer Science+Business Media New York 2012
Abstract Overproduction of nitric oxide (NO) plays an important role in glutamate-induced excitotoxicity. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor. The aim of this study is to explore whether ADMA antagonizes the excitotoxicity of glutamate to neuronal cells and the underlying molecular mechanisms. In this work, we investigated the effects of ADMA on glutamate-induced toxicity in neuronal cells by studying PC12 cells, a clonal rat pheochromocytoma cell line. We show that ADMA obviously protects PC12 cells against glutamate-induced cytotoxicity and apoptosis. We also found that ADMA treatment results in prevention of glutamate-induced mitochondrial membrane potential loss and caspase-3 activation. Moreover, ADMA prevents glutamate-caused down-regulation of bcl-2 protein expression. These results indicate that ADMA protects against glutamate-induced apoptosis and excitotoxicity and the underlying mechanism may be involved in preservation of
X.-Y. Wang (*) Department of Neurology, Third Clinical Hospital, China Three Gorges University, 60 Qiaohu 1st Road, 443002 Yichang, China e-mail: [email protected] X.-Y. Wang Department of Neurology, Gezhouba Central Hospital, 443002 Yichang, China J. Zhao Department of Physiology, Medical College, University of south China, Hengyang, 421001 Hunan, China H.-W. Yang Department of Physiology, college of medical sciences, China Three Gorges University, 443002 Yichang, China
mitochondrial function by up-regulating the expression of bcl-2. Our study suggests a promising future of ADMAbased therapies for neuropathologies associated with an excess of NO. Keywords Asymmetric dimethylarginine . Apoptosis . bcl-2 . Excitotoxicity . Glutamate . Nitric oxide
Introduction Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS) where it acts upon ionotropic (N-methyl-D-aspartate [NMDA] and 2-amino-3-hyroxy-5methylisoxazole proprionic acid [AMPA]) or metabotropic (mGlu1–mGlu8) receptors. It plays a key role in long-term potentiation and cognitive functions such as learning and memory (Aarts and Tymianski 2003). However, alterations in glutamate homeostasis can evoke neuronal dysfunction and even damage or death through the generation of excitotoxic cascades (Choi et al. 1988; Dong et al. 2009). Glutamate-induced excitotoxicity is not only involved in acute neural trauma such as ischemia, spinal cord injury, head trauma, and epilepsy, but also linked to neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD) (Lipton and Rosenberg 1994; Hamilton and Attwell 2010; Dobrek and Thor 2011). Thus, neuroprotection against glutamate-induced neurotoxicity has become a t
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